Our general hypothesis is that nutritional factors and inactivity play significant roles in the development of sarcopenia. Thus, age-specific prolonged interventions including nutritional manipulations and/or exercise may help to reduce, stabilize, or even reverse the loss of muscle mass and strength with age. However, previous studies attempting to improve muscle mass in older subjects using nutritional supplementation had little success, due to a trend for elders to compensate for the energy delivered by nutritional supplements with reduced food intake. Therefore, effective nutritional supplements for the elderly should be more anabolic than the same amount of ordinary food, to limit the caloric content and maximize the anabolic efficiency (anabolic effect/energy delivered). Our preliminary data indicate that essential amino acids are the most efficient nutrients for the acute stimulation of muscle protein anabolism, and that long term utilization may also improve muscle mass in older subjects. Additionally, inactivity is another likely contributor to sarcopenia. Exercise increases not only muscle mass and strength, but also energy expenditure. Hence, exercise may improve the response of muscle to nutritional supplementation in older subjects via increased energy requirements and food consumption, thereby allowing for the achievement of true supplementation. Although resistance exercise is the most anabolic form of physical activity, compliance in the outpatient setting may be disappointing. Aerobic exercise is more appealing and easier to implement in the older population. Our preliminary data indicate that aerobic exercise acutely increases muscle protein synthesis, normalizes muscle perfusion, and reduces the age-related insulin resistance of muscle proteins. Thus, aerobic exercise may improve muscle protein metabolism, strength, function and even mass in older people, particularly when combined with nutritional interventions. We will test the following specific hypotheses in older sedentary subjects: 1. A highly efficient nutritional supplement will increase, with prolonged treatment, muscle mass and strength by stimulating net muscle protein synthesis. 2. Progressive aerobic training will increase muscle strength and function by stimulating muscle protein turnover and improving muscle perfusion and muscle quality. 3. The highly efficient nutritional supplementation combined with progressive aerobic training will increase muscle mass, strength, and function more than either intervention alone by additively stimulating net muscle protein synthesis, and improving muscle perfusion and muscle quality. Our goal is to establish if specific interventions that can acutely increase muscle protein synthesis can also effectively translate into increased muscle mass and performance in older sedentary people. PUBLIC HEALTH RELEVANCE: Our general goal is to find simple and safe interventions to prevent and treat the loss of muscle mass, strength, and function in older persons. Muscle weakness with aging leads to frailty, disability and loss of independence, increasing the risk of institutionalization and death, and greatly increasing healthcare costs. Based on our preliminary data, we propose that prolonged nutritional supplementation with highly effective, age-specific supplements and/or endurance training will enhance muscle mass, strength and function in older persons by increasing muscle growth and quality.